This application addresses broad Challenge Area 03: Biomarker Discovery and Validation, and the specific Challenge Topic 03-MH-101: Biomarkers in Mental Disorders. Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent behavioral disorder of childhood affecting about 6 million school children and perhaps 10 million adults in the US. ADHD is however a very controversial disorder. Some critics question its validity, others argue that the criteria are too broad, too subjective, or not developmentally sensitive. Pediatric bipolar disorder is an even more controversial diagnosis, associated with widespread disparity between experts in criteria and prevalence rates. The aim of this Challenge Grant is to rigorously test our preliminary findings identifying three potential biomarkers. Two of these appear to be markers for ADHD that had perfect accuracy in discriminating between children with ADHD and controls in limited samples. However, these studies only included boys aged 9 - 12 who met criteria for Combined Subtype, and had been previously treated with methylphenidate (MPH). It is critical to ascertain if these findings can be replicated in an independent sample, extended to girls, older and younger individuals, to all ADHD subtypes, and to ADHD subjects with no prior history of psychotropic treatment. The third marker appears to identify children with bipolar disorder, and in a sample of 103 subjects distinguished bipolar from ADHD and controls with 94% sensitivity and specificity. Bipolar children in this sample met strict operational criteria for DSM-IV bipolar disorder. Hence, we propose to rigorously evaluate three potential biomarkers that address two severe but overlapping challenges. On one hand, there is the challenge of identifying where normal ends and where ADHD begins. On the other hand, there is the challenge of determining whether hyperactive, disruptive, aggressive and emotionally labile children have ADHD, bipolar disorder, both, or something entirely different. The first biomarker emerged from a state-of-the-art non-linear analysis of head movements and positional stability. The maximum Lyapunov exponent discriminated 62 ADHD children from 62 matched controls with perfect accuracy (ROC = 1.0). The second marker is a measure of regional T2-relaxation time (T2RT) in left putamen and right dorsolateral prefrontal cortex. The third marker is a composite of actigraph measures of sleep, daytime hyperactivity and circadian dysregulation. Children with DSM-IV bipolar disorder had greater impairments in sleep and circadian rhythmicity than children with ADHD and comorbid mood disorders. The validity of these potential markers will be tested in a mixed gender sample of 160 children (80 ADHD, 40 bipolar, 40 control) between 6-17 years of age (n=80 neuroimaging). Identifying markers that distinguish ADHD from normal and ADHD from bipolar could have an enormous impact on the field. These findings (if further validated) can lead to a revamping of clinical criteria, and rapidly advance research into the genetics, etiology, pathophysiology and treatment of ADHD and pediatric bipolar disorder. This Challenge Grant is designed to test the validity of two potential biomarkers that in preliminary studies distinguished boys with Attention-Deficit Hyperactivity Disorder (ADHD) from controls with complete accuracy. A third biomarker will also be studied that distinguished children with bipolar disorder from subjects with ADHD and healthy normal controls with 94% sensitivity and specificity. These markers will be assessed in 160 children (6-17 years of age) from both genders. Eighty subjects will have ADHD, 40 bipolar disorder, and 40 will be healthy controls.